Polytropic MuLVs are formed by recombination of ecotropic MuLVs with endogenous envelope sequences present in the genomes of inbred mouse strains. The viruses exhibit an altered infectious host range and utilize a cell surface receptor distinct from the receptor utilized by ecotropic MuLVs. In several instances polytropic MuLVs have been directly implicated in pathogenesis, including the induction of proliferative, immunological, and neurological disorders. The generation of variants after infection results in a mixed retrovirus infection. One aspect of the project involves studies of the interactions of retroviruses in mixed infections. Upon co-inoculation of polytropic and ecotropic MuLVs in mice we have observed profound effects on the infectious spread of the polytropic virus, concomitant with a very rapid induction of neurological disease not observed after inoculation with either virus alone. A common effect of mixed infections resulting in neurological disease is a greatly enhanced spread of the polytropic virus in tissues peripheral to the central nervous system (CNS). This phenomenon is mediated by pseudotyping of polytropic viral genomes within ecotropic virus particles. Polytropic MuLVs initially detected in the CNS are also pseudotyped, however a subsequent rapid spread of the virus in the CNS appears to proceed by polytropic virions that are not pseudotyped. This rapid spread is nearly coincident with the onset of neurological symptoms. Neurological disease is evident in mice inoculated as a mixture of ecotropic MuLVs with a number of different polytropic MuLVs, suggesting that neuropathogenicity may be a general property of polytropic MuLVs. In addition, our studies suggest that a threshold of peripheral replication is required for invasion of the CNS, and that spread of the polytropic virus through interaction of the polytropic receptor-binding protein with receptors on CNS cells may be a requirement for the induction of neuropathology. Another aspect of our studies involves the precise identification of endogenous retroviruses in mice that participate in recombination giving rise to recombinant polytropic viruses. Different ecotropic viruses specifically recombine with different endogenous proviruses to give rise to the recombinants. Determination of the precise sequences that participate in recombination is essential to understanding characteristics of the endogenous viruses that facilitate this process. Such identification has been elusive because of the very close similarity of the endogenous viruses as well as the rapid rate of evolution of the viruses during replication. We have isolated most of the endogenous proviruses in NFS/N mice that could potentially give rise to the recombinant viruses and found that nearly all could be distinguished from one another by sequence heterogeneity in their env genes. Examination of the sequences of polytropic viruses derived from these mice in a manner that minimized the number of replication cycles has, for the first time, precisely identified proviruses that give rise to the recombinant viruses. Furthermore, phylogenetic comparisons have identified a new group of endogenous polytropic proviruses. This group exhibits characteristics indicative of viruses that were progenitors to the polytropic proviruses that have thus far been described in the literature. We have found that these proviruses participate in recombination to generate polytropic MuLVs, even though many of their descendants have been reported to be defective.